Currently, immunosuppressive agents such as steroids, cyclosporin A, tacrolimus, mycophenolate mofetil, mizoribine, or deoxyspergualin have been used to treat or prevent graft rejection reaction, autoimmune diseases, allergic diseases, and various types of autoimmune diseases.
In recent years, it has been known that when a steroid drug that has been used as an anti-inflammatory agent for a long time is administered in a large amount, it acts on macrophages and lymphocytes to exhibit immunosuppressive activity.
Cyclosporin A and tacrolimus suppress production of cytokines acting as a lymphocytes controlling factor to exhibit immunosuppressive activity.
Cyclosporin A is administered to suppress rejection occurring after kidney, liver, bone marrow, or cardiac transplantation, or to treat Behcet's disease, psoriasis, aplastic anemia, and nephrotic syndrome.
Tacrolimus is used as a more potent cytokine production-suppressive agent, and is administered to suppress rejection occurring after kidney, liver, bone marrow, or cardiac transplantation, or to treat atopic dermatitis and myasthenia gravis.
Mycophenolate mofetil and mizoribine exhibit immunosuppressive activity as a result of a nucleic acid antimetabolite-effect on lymphocytes.
Mycophenolate mofetil is used to suppress rejection occurring after kidney transplantation. Mizoribine is used to suppress rejection occurring after kidney transplantation and to treat nephrotic syndrome, lupus nephritis, and chronic rheumatoid arthritis.
Deoxyspergualin inhibits production of antibodies and the functions of lymphocytes to exhibit immunosuppressive activity. It is used to treat rejection occurring after kidney transplantation.
Such an immunosuppressive agent is also useful for autoimmune diseases other than the aforementioned diseases. Cyclosporin A, for example, has been reported useful for diseases such as atopic dermatitis, autoimmune hepatitis, Crohn's disease, ulcerative colitis, myasthenia gravis, multiple sclerosis, rheumatoid arthritis, and insulin dependent diabetes mellitus, in addition to the aforementioned diseases.
By the way, in the aforementioned diseases, an immune phenomenon that has a harmful effect on a patient him/herself takes place via antigen presentation, causing pathological conditions. In the case of autoimmune disease, for example, an autoantigen or a foreign antigen similar to the autoantigen is presented to an immunocompetent cell by a dendritic cell that is one of antigen-presenting cells. It is considered that an immune response to the autoantigen is thereby induced, and that disruption of autotissues takes place.
Also, in rheumatism that is an inflammatory disease, accumulation of dendritic cells acting as antigen-presenting cells is observed in the affected region of the joint of a patient, and thus it is considered that such antigen presentation is associated with the development and the deterioration of the disease.
When T cells recognize cells expressing a target antigen, such recognition is conducted via MHC (major histocompatibility (gene) complex). Thus, for autoimmune diseases and inflammatory disease also, it is considered that antigen presentation is associated with activation of T cells in affected regions and tissue injury. Based on these facts, autoimmune diseases and the like can be treated or prevented by inhibiting the presentation of an autoantigen or a foreign antigen similar to the autoantigen.
Moreover, it has been reported that immune tolerance is induced by the difference in maturation stages of dendritic cells presenting antigens. Mature dendritic cells induce effector T lymphocytes having cytotoxicity and cytokine producing ability. In contrast, it is considered that immature dendritic cells induce regulatory or suppressive T cells, thereby playing an important role in inducing and maintaining immune tolerance. Accordingly, it is considered that if the maturation of cells presenting antigens (hereinafter referred to as antigen-presenting cells) is suppressed, immature dendritic cells increase, and that immune tolerance is thereby induced.    [Non-Patent Document 1] Ludewig, B. et al., Current Opinion in Immunology, vol. 13, p. 657 (2001)    [Non-Patent Document 2] Thomas, R. et al., Journal of Leukocytes Biology, vol. 66, p. 286 (1999)    [Non-Patent Document 3] Menekigaku Illustrated (5th edition), Roitt, I. et al., edited and translated by Fujio Tada, Nankodo Co., Ltd., (2000), pp. 128-131 and pp. 355-358    [Non-Patent Document 4] Ralph, M. S. et al., Proceedings of the National Academy of Sciences of the United States of America, vol. 99, 351 (2002)